Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Peroxisome proliferator-activated receptor-beta/delta (PPAR-beta/delta) is a transcription factor that belongs to the PPAR nuclear hormone receptor family. There is little information about the effects of the immediate administration of specific ligands of PPAR-beta/delta (e.g., GW0742) in animal models of myocardial I/R injury. Using a rat model of regional myocardial I/R in vivo, we have investigated the effects of immediate administration of GW0742 on myocardial infarct size. ⋯ The reduction in infarct size afforded by GW0742 was not reduced by the competitive irreversible PPAR-alpha antagonist GW6471 (1 mg/kg i.v., 15 min before ischemia). GW0742 (30 microg/kg i.v.) reduced the I/R-induced (a) decrease in the phosphorylation of Akt and glycogen synthase kinase-3beta, (b) nuclear translocation of the p65 subunit of nuclear factor-kappaB (activation of nuclear factor-kappaB), and (c) increase in the expression of iNOS and cyclooxygenase-2. Thus, immediate administration of the PPAR-beta/delta ligand GW0742 during reperfusion reduces myocardial infarct size in the rat by a mechanism that may involve inhibition of the activity of glycogen synthase kinase-3beta secondary to activation of the Akt pathway.
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Adhesion of polymorphonuclear neutrophils (PMN) to coronary endothelium is a key event for cardiac ischemia/reperfusion injury. Adhesion molecules are normally harbored within the glycocalyx, clothing every healthy vascular endothelium, but shed by ischemia/reperfusion. Our aim was to show whether protection of the glycocalyx with either hydrocortisone or antithrombin can reduce postischemic leukocyte adhesion. ⋯ Activation of PMN upon coronary passage was not influenced. Preservation of the glycocalyx mitigates postischemic PMN adhesion. Preconditioning with either hydrocortisone or antithrombin should, thus, alleviate vascular leakage, tissue edema, and inflammation.
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Multicenter Study
Early and small changes in serum creatinine concentrations are associated with mortality in mechanically ventilated patients.
Emerging evidence suggests that minor changes in serum creatinine concentrations are associated with increased hospital mortality rates. However, whether serum creatinine concentration (SCr) on admission and its change are associated with an increased mortality rate in mechanically ventilated patients is not known. We have conducted an international, prospective, observational cohort study enrolling adult intensive care unit patients under mechanical ventilation (MV). ⋯ Among patients with SCr0 less than or equal to 1.40 mg/dL, DeltaSCr greater than 0.31 discriminated mortality (56% vs. 34%, P < 0.001). In multivariate analysis, geographic area, advanced age, severity of illness, reason for MV, and cardiovascular and hepatic failure were also associated with mortality. Our study suggests that SCr0 greater than 1.40 mg/dL and, in patients with low baseline SCr, a DeltaSCr greater than 0.31 are predictors of in-hospital mortality in mechanically ventilated patients.
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Treatment options to improve resuscitability and neurological prognosis after cardiac arrest (CA) are limited. Hydrogen sulfide has demonstrated remarkable improvements in outcomes in small animal models of severe hypoxia or hemorrhage. We investigated the influence of sodium sulfide (Na2S), a liquid hydrogen sulfide donor, on resuscitability, postresuscitation hemodynamics, and neurological performance in a porcine model of prolonged CA and cardiopulmonary resuscitation. ⋯ High-dose Na2S significantly decreased microglial activation in striatal areas, although this did not translate into improved neurological outcome. Although animals receiving Na2S developed higher troponin T serum levels, these differences remained insignificant. In this investigation, Na2S did not improve resuscitability but significantly compromised postresuscitation hemodynamics.
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Increased apoptotic cell death is believed to play a pathological role in patients with sepsis and experimental animals. Apoptosis can be induced by either a cell death receptor (extrinsic) or a mitochondrial (intrinsic) pathway. Bid, a proapoptotic member of the Bcl-2 family, is thought to mediate the cross talk between the extrinsic and intrinsic pathways of apoptosis; however, little is known about the action of Bid in the development of apoptosis and organ-specific tissue damage/cell death as seen in polymicrobial sepsis. ⋯ Bid-deficient mice exhibit significantly reduced apoptosis in the thymus, spleen, and Peyer patches compared with background mice after sepsis. Furthermore, Bid-deficient mice had significantly reduced systemic and local inflammatory cytokine levels and improved survival after sepsis. These data support not only the contribution of Bid to sepsis-induced apoptosis and the onset of septic morbidity/mortality, but also the existence of a bridge between extrinsic apoptotic signals, e.g., FasL:Fas, TNF:TNFR, and so on, and the intrinsic mitochondrial pathway via Bid-tBid activation during sepsis.